Parkinson's disease (PD) is a neurodegenerative disease characterized by impaired movement. One of the most common and disabling symptoms of PD is fatigability; fatigue that is induced by activity or exercise PD fatigability has deleterious effects on independence and quality of life in patients who have PD, as well as their caregivers. Despite these negative effects on patients and the increasing financial burden placed on society, few objective studies have investigated the underlying mechanisms of fatigability in PD. Specifically, we propose to define the roles of central mechanisms (cortical and spinal components) and peripheral mechanisms (muscular components) in PD fatigability. The long-term objective is to examine the neuromuscular mechanisms underlying fatigability by analyzing muscle activation and torque production obtained from people who have PD who report activity-related fatigability. To accomplish this goal, we will pursue the following specifi aims: Aim 1 is to differentiate between central and peripheral contributions to fatigability in people who have PD compared to age-matched and younger control subjects. Aim 2 is to evaluate the Dopa-responsiveness of PD-related fatigability. People who have PD, healthy young subjects, and age-matched control subjects will participate in the proposed study. Knee joint torque and electromyographic activities of the quadriceps and hamstrings will be measured during maximal isometric knee extension and flexion contractions. An isometric fatiguing protocol will be performed using the Biodex system. Superimposed electrical muscle stimulation will be used before and after the fatiguing protocol to determine central versus peripheral contributions to torque. Dopa-responsiveness of fatigue will be assessed by comparing the fatigability of each subject with PD on anti-PD medication (ON-med) with his or her fatigability after temporary withdrawal of medication (OFF-med). The study is intended to increase our understanding of the mechanisms underlying PD fatigability which will lead to better assessment tools to measure fatigability and the development of targeted, evidence-based interventions to relieve this disabling symptom of PD. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) affects over 1.5 million Americans and is rapidly growing with 75,000 new cases diagnosed annually. PD is associated with motor impairments including rigidity and fatigue, which greatly diminish patients' quality of life. As th elderly population continues to expand, the prevalence of PD will continue to increase resulting in greater caregiver burden and financial demand. The proposed study is of significant relevance to public health and to the mission of NIH.